Metronomic convection enhanced delivery of intrathecal chemotherapy using an implanted magnetic breather pump (MBP) for leptomeningeal carcinomatosis

ABSTRACT

A magnetically controlled pump is implanted into the cerebrospinal fluid of a patient and delivers a plurality of medicating agents at a controlled rate corresponding to the specific needs of the patient. The current invention comprises a flexible double walled lumen, intratumoral catheter which will be implanted. Spinal fluid drawn from the patient is analyzed. Medication is delivered on a continuous metronomic basis into the CSF via an internalized pump. CSF is removed and analyzed for VEGF and other cytokines via spectrophotometer analysis or a lab on a chip. The operation of the apparatus and hence the treatment is remotely controlled based on these measurements and displayed through an external controller.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to the field of implantable drug delivery systems,specifically a magnetically controlled aspirating pump and a method fordelivering metronomic intrathecal chemotherapy into the spinal fluid ofa patient using the same.

2. Description of the Prior Art

When tumors develop inside the human body, the options for availabletreatment are fairly narrow. This is even more so when the tumordevelops inside a vital organ such as the brain or spinal cord. Diseasessuch as leptomeningeal carcinomatosis that develop in or around theleptomeninges of the brain and spinal cord are notoriously difficult totreat and thus have a high mortality rate.

Leptomeningeal carcinomatosis is caused by metastatic seeding of theleptomeninges from systemic cancer, usually breast, lung, and melanoma.If left untreated, patients typically die within two months ofdiagnosis. Traditionally, the options for treating leptomeningealcarcinomatosis in or around the spinal cord include radiation,chemotherapy, and local intrathecal or intraventricular chemotherapy.Each of these prior methods of treating leptomeningeal carcinomatosishave had some form of success in the past, however each of them alsocontain various deficiencies and pitfalls that make them less than idealwhen treating a patient. What is needed is a more reliable, easier, andeffective process for treating leptomeningeal carcinomatosis.

Radiation is a common mode of treatment for leptomeningealcarcinomatosis. It is usually given as a fractionated dosage treatment,covering a certain field encompassing the spinal column, over a periodof six weeks. Spatially localized forms of radiation, includingcyberknife and gamma knife have been used with varying levels of successat focal areas of leptomeningeal enhancement. Although radiation isstill widely acknowledged as the one of the most effective modes ofadjunctive treatment, it suffers from the disadvantage of limitedfractions and applications.

Another method used to combat brain tumors is systemic chemotherapy.Systemic chemotherapy is a viable option as an adjunct to radiation.However, it is limited in efficacy in metastatic seeding the spinalcolumn by: 1) delivery across the blood brain/spine barrier, 2)development of drug resistance by the cancer cells, and 3) systemicside-effects from the chemotherapeutic agent. Because the bloodbrain/spine barrier is only partially broken down in the presence ofleptomeningeal carcinomatosis, it still impairs the effective deliveryand transport of systemic chemotherapy into the spinal fluid. Lastly,chemotherapy is distributed systemically throughout the entire body.Because the whole body of the patient undergoes the treatment (not justthe spinal related area), undesirable side effects such as nausea,diarrhea, hair loss, and loss of appetite and energy may occur. Some ofthe side effects are so strong in some patients that chemotherapy isunavailable to them as a treatment and thus decrease their overallchances for survival.

In fact, even with radiation and systemic chemotherapy, the mediansurvival of a patient with leptomeningeal carcinomatosis is currentlyonly approximately six months.

Recently, intrathecal chemotherapy using either DepoCyt, a long actingliposomal Ara-C and produced by Enzon Pharmaceuticals of Japan, ormethotrexate has been used with a mild degree of success. Most patientsare treated with interval injections of chemotherapy via an Ommayareservoir or via a lumbar puncture. Inevitably the tumor recurs despitetreatment. Consequently, the patients may develop hydrocephalus, andeventually death.

The underlying hypothesis of using polypharmacy employed by the currentinvention is based on the premise that combination treatment is betterthan monotherapy. Moreover, the concept of controlling the delivery ofthe polypharmacy in a controlled metronomic methodology is advocated asa method of better control. Thus, a first step in administrating acytotoxic agent is to determine the maximum tolerated dose (MTD).However, when used in traditional treatment methods, such aschemotherapy, the cytotoxic agents are delivered to the patient in amanner that allows the cytotoxic agents to be distributed more or lessglobally throughout the body of the patient. Relatively large doses ofthe drugs are required since only a small fraction of the administereddose will be present at the desired site at any given time. Theremainder of the dose will be in the other parts of body. Moreover, amajor problem with conventional chemotherapy is lack of specificity intargeting the cancer cell.

The use of large doses of toxic agents often leads to serious anddebilitating side effects. Moreover, the global administration of drugsis often not compatible with combination therapies where a number ofmedicating agents are used synergistically to treat tumors or otherconditions. Thus, the global administration of medicating agents totreat tumors and other such medical conditions is an inefficient andoften dangerous technique that often leads to severe or debilitatingside effects.

Recently, there have been some developments in the field of medical drugdelivery systems. The majority of these systems have taken the form of apump or other device that releases a variety of drugs into variouspositions in and around the body of a patient.

For example, many of the devices found in the prior art are much likethe inventions disclosed in U.S. Pat. Nos. 6,852,104 (“Blonquist”) and6,659,978 (“Kasuga”). Both of these inventions comprise a small tank forholding a drug regimen, a pump for pumping the drug regimen into thebody of a patient, and some sort of electronic control system thatallows the user to program the specific amount and at what time acertain drug regiment is to be administered. While these apparatuses maybe ideal for administering certain drugs such as insulin to patients whoare diabetic, they are neither designed nor suitable for directlytreating leptomeningeal carcinomatosis within the brain and spinal cordof a patient.

Other prior art examples such as U.S. Pat. Nos. 5,242,406 (“Gross”) and6,571,125 (“Thompson”) offer smaller, more convenient alternatives foradministering drugs, however their reliance on maintaining a specificset of pressures and a certain amount of electrical current respectivelymakes them too complicated and prone to error.

U.S. Pat. Nos. 7,351,239 (“Gill”), 7,288,085 (“Olsen”), and 6,726,678(“Nelson”) disclose a pump or reservoir that is capable of deliveringmedicating fluids to the brain, but requires that the pump and drugreservoir be implanted in different locations within the patient. Thisconfiguration is not only uncomfortable for the patient, but alsoincreases the possibility of infection and unnecessarily complicates theimplanting procedure. Additionally, every time the patient needs thedrug reservoir refilled or the pump battery replaced, the physician mustinvasively re-enter the patient. Finally, none these prior methodsdisclose a way of measuring the value of the vascular endothelial growthfactor (VEGF) so as to enable tailoring of the delivered medical agent,toxicity to meet the needs of a specific individual patient.

What is needed is a device and a method that is capable of deliveringmedicating agents directly to the cerebrospinal fluid (CSF) of the brainand spinal cord that is easy to operate and relatively simple toimplant, while at the same time, is easy to maintain throughout thepatient's treatment cycle and customize to the patient's specific needswithout causing all of the negative side effects associated withprevious treatment methods.

BRIEF SUMMARY OF THE INVENTION

A magnetically controlled pump is implanted into the cerebrospinal fluid(CSF) of a patient and delivers a dose of therapeutic agent at acontrolled rate corresponding to the specific needs of the patient forleptomeningeal carcinomatosis.

The illustrated embodiment of the invention solves the above limitationsin the prior art and other problems by effectively treatingleptomeningeal carcinomatosis using a multi-delivery catheter implantedinto the CSF. Through at least two proximal ports, an internalizedexternally controlled pump will deliver up to four different kinds ofchemotherapeutic agents at a controlled rate corresponding to thespecific needs of the patient. Spinal fluid drawn from the patient isanalyzed. The operation of the apparatus and hence the treatment isremotely controlled based on these measurements and displayed through anexternal controller.

The microdelivery pump has three components: a proximal head reservoir,a catheter extending from the proximal head, and an analyzer unitconnected to the catheter. The proximal head is comprised of a catheterinserted into the CSF, the illustrated embodiment of the inventioncomprises a proximal delivery device which will be implanted into thelateral ventricle of the frontal horn or intrathecally. The head cap ofthe pouch also contains a valve that allows the reservoir of theapparatus to be refilled and for cerebrospinal fluid that has been drawninto the pouch to be withdrawn from the spinal region of the patient viaa suction nozzle. In this way, the pump also enables a decompressivemechanism for controlling the intratumoral pressure, and for samplingfluid.

An embodiment of the current invention involves a multideliverycatheter. Conventional catheters used for convection enhanced deliveryfor tumors caused by leptomeningeal carcinomatosis consist of either asingle port in the tip of peritoneal tubing used forventriculoperitoneal shunts, or a proximal shunt catheter with multipleholes cut within 1 cm of the tip of catheter tip.

The medication intake line and the cerebrospinal fluid return linecoupled to the head cap of the apparatus are housed within a siliconecatheter. The catheter runs underneath the skin of the patient, in theposterior auricular location to the neck, and emerges from the patientin an easily accessible location such as beneath the head of theclavicle as in a Port-A-Cath. The catheter is coupled to an analyzerunit, thus forming a drug delivery system.

The analyzer unit is a housing means for several key components of theapparatus. Cerebrospinal and/or tumor fluid that has returned from thepatient passes through a lab-on-a-chip which measures and monitors thevascular endothelial growth factor (VEGF) levels for indications ofprogress or regression of the patient's tumor burden. The user orphysician operating the apparatus can then adjust or change the drugregimen the patient is receiving based on these measurements. Alsocoupled to the unit are four piezoelectric pumps that send up to fourdifferent medicating agents through the catheter. A Blue Tooth® chipalso allows the unit to be controlled by a physician from a remotelocation. Flash memory chips and an artificial intelligence processorcomplete the circuitry needed in order to provide the patient with aneffective, easy to use apparatus that delivers medicating agents at aset and controlled rate. Finally, the analyzer unit or chemotherapypumping device (CPD) includes a long lasting lithium ion battery thatpowers the unit itself.

It is therefore an object of the invention to provide a patient withconstant medication without re-implanting a catheter every time apatient needs to be treated.

It is another object of the invention to provide a metronomic continuousdelivery of a medicating agent.

It is a further object of the invention to provide users and physiciansin charge of a patient's treatment instant monitoring and feedback ofvarious tumor parameters in order for the patient's treatment to bechanged or adjusted accordingly.

It is a further object of the invention to provide patients with tumorscaused by leptomeningeal carcinomatosis an effective way of treatingtheir affliction while minimizing the side effects of chemotherapy.

Another object of the invention is to enhance the mechanism of vectorialchange of tumor escape mechanism by introducing a sufficient tumorantigen to stimulate the immune system of the patient.

Another object of the invention is to assist in irrigating the solidtumor by increasing cell adhesion molecules which are used for theadherence of cytotoxic cells to target cells before lysis can ensue. Themalignant cells cannot bind to cytotoxic cells. The use of the apparatuswill improve and enhance such a process.

Yet another object of the invention is to administrate biologicalresponse modifiers (BRMs) with an improved dose, local delivery andscheduling on a case-specific basis using the programmablemicrocontroller and its associated valve mechanism.

Another object of the invention is to allow the clinician the ability toprescribe an optimal biological dose (OBD) of medicating agent asopposed to maximum tolerated dose (MTD) of medicating agent by the useof an apparatus control mode defined by its programmability and itslogic, which is embedded in microcontroller look-up-tables.

Another object of the invention is to incorporate the pharamacokineticand pharmacodynamic parameters associated with chemotherapeutic agentsso as to achieve the desired results without the toxic side effectsknown to those familiar with the art.

Another object of the invention is to modulate and modify the output ofthe medicating agent during treatment by changing the procedure in realtime through the use of the command structure of the microcontrollerlook-up-tables with the use of a communication link built into theapparatus.

Another object of the invention is to regulate the rate of dispensationof the medicating agent by modifying the duty cycle of the valve locatedin the apparatus.

Another object of the invention is to regulate the intake of the tumorBRMs due to their pleiotropic nature, and allow for processes andmechanisms to develop by reducing or enhancing the various agents in themedicating apparatus (MBP), hence providing a treatment specific to thepatient (e.g. tumor, size, lysis, etc).

Another object of the invention is to provide the clinician a way toallow the expression of BRMs cascade effects (due to the communicationof cytokines as messengers with their synergistic, additive orantagonistic interactions that affect the target tumor cells).

Another object of the invention is to provide scheduling of medicatingagents such as cyototoxic chemotherapy, BRMs, and others as based ontheir toxicity, and to allow for measures such as bioavailability,solubility, concentration, and circulation based on locality, both ofwhich are the improved approach to the elimination of leptomeningealcarcinomatosis.

Another object of the invention is to address the individual differencesof various tumors based on the disease stage, immune factors, bodyweight, age and chronobiology through the ability of the apparatus tolocally administer the agents, dosing, and scheduling.

Another object of the invention is to provide an effective mode ofadministrating BRMs with chemotherapy as a combination therapy by makingavailable a local administration of different IFNs with IL-2 or IL-2 incombination with monoclonal antibodies and tumor necrosis factors(TFNs), and scheduling by the use of the invention under metromonicregiment.

Another object of the invention is to enable drug manufacturers toevaluate the effectiveness of its drug during animal and clinicalstudies by providing the details and feedback on the use, dose, cycle,circadian time effects and the entire pharmacokinetic andpharmacodynamic behavior of the medicating agents not as verbal reportsof symptomalogy chronicles by the patient, but as a biological measureof tumor responses to the agents.

Another object of the invention is to provide a method and apparatus forlocal administration of BRMs, cytotoxic chemotherapeutic agents, andothers, to enhance mechanisms that support overlapping effects inreducing tumor burden and elimination of tumors. To induce an improvedresponse by the use of biomodulators (augmenting the patient'santi-tumor response via production of cytokines), decreasing suppressormechanisms, increasing the patient's immunological response, limitingthe toxicity of such agents (by the locality), maximizing the dose,increasing susceptibility of cells membrane characteristics for improvedchemotherapy results at the site, and decreasing the tumor's ability tometastasize.

The above characteristics are measurable elements since dosing andscheduling improves the effectiveness of chemotherapy on malignant cellsand reduces the exposure of such toxins to normal tissues. Oneembodiment provides improved immunomodulation with relatively littleimmuno-suppression. Another object of the invention is to provide fordefining an improved dose and schedule of biological agents to maximizethe anti-tumor effects of each agent while not increasing toxicity tothe patient. Treatment modality by the use of combination therapy andlocal administration of such agents on a specific schedule is one of thebenefits of the invention.

It is yet another object of the invention to provide preoperativesimulation of the infusion of medicating agents into the spinal fluid tomaximize infusion efficiency and minimize local toxicity by means of adiffusion model. The use of a drug diffusion model (DDM) inside thecranial vault permits a systematic design of targeted drug delivery intothe ventricles and spinal subarachnoid space (SAS). Based on thecomputational fluid dynamics (CFD) approach, the model permits accurateprediction of drug diffusion in the cranial vault of the human brainbased on the established transport and chemical kinetics models thatdescribe the CSF motion in the brain. The model can be simulated in acomputer-aided brain analysis before the actual placement procedure,thus reducing the need for trial-and-error animal experimentation orintuitive dosing in human trials.

Finally, it is yet another object of the invention to provide operatingphysicians a method of treating leptomeningeal carcinomatosis withouthaving to worry about the medicating agent being diluted or hindered bythe blood brain barrier (i.e. direct antibody injection into the tumor).

While the apparatus and method has or will be described for the sake ofgrammatical fluidity with functional explanations, it is to be expresslyunderstood that the claims, unless expressly formulated under 35 USC112, are not to be construed as necessarily limited in any way by theconstruction of “means” or “steps” limitations, but are to be accordedthe full scope of the meaning and equivalents of the definition providedby the claims under the judicial doctrine of equivalents, and in thecase where the claims are expressly formulated under 35 USC 112 are tobe accorded full statutory equivalents under 35 USC 112. The inventioncan be better visualized by turning now to the following drawingswherein like elements are referenced by like numerals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 a is a diagrammatic cross sectional view of a patient's bodyafter the implantable pump unit has been successfully implanted thepatient's lateral ventricle and the CPD has been implanted beneath theskin in the chest cavity.

FIG. 1 b is a block diagram of the architecture of the external controlunit which communicates with the implanted apparatus.

FIG. 1 c is a diagram which illustrates the implantable pouch and itsassociated communications controller.

FIG. 2 is an isometric view of the CPD.

FIG. 3 a is a front view of the CPD.

FIG. 3 b is a left side view of the CPD.

FIG. 3 c is a right side view of the CPD.

FIG. 3 d is a bottom view of the CPD.

FIG. 4 a is a right side view of the CPD highlighting the deliveryconnector.

FIG. 4 b is a magnified view of the delivery connector of FIG. 4 a.

FIG. 4 c is a bottom view of the CPD with an ampoule bay highlighted.

FIG. 4 d is a magnified view of an ampoule bay of FIG. 4 c.

FIG. 5 is a partially exploded view of the CPD.

FIG. 6 is a fully exploded view of the CPD.

FIG. 7 a is a perspective view of the top of the induction chargerassembly and pump electronics assembly coupled together.

FIG. 7 b is a perspective view of the bottom of the induction chargerassembly and pump electronics assembly coupled together.

FIG. 8 a is a perspective view of the top of the pump electronicsassembly.

FIG. 8 b is a perspective view of the bottom of the pump electronicsassembly.

FIG. 9 a is a perspective view of the top of the induction chargerassembly.

FIG. 9 b is a perspective view of the bottom of the induction chargerassembly.

FIG. 10 a is an isometric view of the implantable leptomeningeal pump.

FIG. 10 b is a diagram which depicts the “electrostatic muscle” definingthe “supply mode” of the implantable spinal pump.

FIG. 10 c is a diagram which depicts the “electrostatic muscle” definingthe “pump mode” of the implantable spinal pump.

FIG. 11 a is an isometric view of the implantable spinal pump with thepump-to-seal interconnect disconnected.

FIG. 11 b is a magnified view of the pump head assembly.

FIG. 12 is a cross sectional view of the implantable spinal pump.

FIG. 13 a is a partially cutaway cross sectional view of the implantablespinal pump with a plurality of injector spines highlighted.

FIG. 13 b is a magnified view of the injector spines in the circledregion 13 a of FIG. 13 a.

FIG. 13 c is a magnified cross sectional view of the inner and outermembranes of the implantable cranium pump.

FIG. 14 a is a side and cross sectional view of a hollow injectorneedle.

FIG. 14 b is a side and cross sectional view of a spiral injectorneedle.

FIG. 15 a is a front view of the pump actuator assembly.

FIG. 15 b is a cross sectional view of the pump actuator assembly.

FIG. 16 a is an exploded bottom view of the pump actuator assembly.

FIG. 16 b is an exploded top view of the pump actuator assembly.

FIG. 17 is a functional block diagram of the pump actuator assembly.

The invention and its various embodiments can now be better understoodby turning to the following detailed description of the preferredembodiments which are presented as illustrated examples of the inventiondefined in the claims. It is expressly understood that the invention asdefined by the claims may be broader than the illustrated embodimentsdescribed below.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the methods, devices,and materials are now described. All publications mentioned herein areincorporated herein by reference for the purpose of describing anddisclosing the materials and methodologies which are reported in thepublications which might be used in connection with the invention.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such disclosure by virtue of prior invention.

The following mathematical symbols used here in refer to its definitionsas follow: Q is infusate flow rate; ρ_(f) is drug fluid density; {rightarrow over (ν)}_(f) is drug fluid velocity in the catheter; μ_(f) isdrug fluid viscosity; D_(b) is bulk diffusivity of drug molecules; ρ_(c)is CSF density; {right arrow over (ν)}_(c) is CSF velocity in theventricular and subarachnoid systems; μ_(c) is CSF viscosity; D_(b) isdiffusivity of drug molecules in CSF; ε is tissue porosity; p isinfusion fluid pressure; {right arrow over (∇)}_(t) is pressuregradient; D_(e) is effective diffusion tensor; C_(f) is Concentration ofdrug; {right arrow over (ν)}_(t) is fluid velocity in the porous tissue;D_(e) is mean effective diffusivity; k is permeability of the braintissue;

is Hydraulic conductivity tensor, which is a function of fluid viscosityμ and effective tissue permeability tensor κ; {right arrow over(ν)}_(t)·{right arrow over (∇)}C_(t) is convection term, D_(e){rightarrow over (∇)}C_(t) is diffusion flux; C_(t)({right arrow over (x)},t)is tissue averaged species concentration; R(C_(t),{right arrow over(x)}) is drug decomposition due to metabolic reaction; S(C_(t),{rightarrow over (x)}) is sink terms due to bio-elimination.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The apparatus is additionally described and disclosed within U.S. patentapplication Ser. No. 12/143,720 filed Jun. 20, 2008, which is hereinincorporated by reference in its entirety.

The implantable pump unit 100 of the illustrated embodiment comprises aninner membrane 107 and an outer membrane 106 as seen in FIG. 13 c. Thespace enclosed by inner membrane 107 is a medication reservoir 129 usedfor storing a medicating agent or a mixture of medicating agents asshown in FIG. 12.

The size and volume of the medication reservoir 129 and thus the spinalpump 100 itself may be varied from patient to patient. A physician willmake a determination of how much medication a particular patient willneed and then the size of the medication reservoir 129 will be madeaccordingly. For example, a patient that needs large doses of medicationwill receive a spinal pump 100 with a larger medication reservoir 129then a patient who only requires a small dose.

Returning to FIG. 13 c, the outer membrane 106 further comprises aplurality of micro pores 112 distributed throughout its entire surface.When the pump 100 is in the intake stroke, spinal fluid is drawn intothe pump 100 through the micro pores 112 due to the pressuredifferential that exists between the inside of pump 100 and thesurrounding area outside of the pump 100. The amount of spinal fluidthat is drawn through the micro pores 112 is kept separated from themedication reservoir 129 by the inner membrane 107 and the lowerportions of the injection spines 108. The volume of spinal fluid that isthen contained between the inner membrane 107 and outer membrane 106then forms a sampling cavity 111. The components of spinal pump 100 ispreferably composed of silicone, as this is the material currently usedfor ventriculoperitoneal shunts. However additional materials such asbiodegradable materials or other composites may be used withoutdeparting from the original spirit and scope of the invention.

The implantable pump unit 100 further comprises a pump head 103 disposedon the top of pump 100 and a pump solenoid 104 disposed at the bottom ofthe pump 100. The detailed parts of the pump head 103 and pump solenoid104 assemblies are shown in FIGS. 15 a-16 b. In FIG. 15 a, the pumpsolenoid 104 is comprised of a coil 119 which can generate magneticfields either reinforcing or opposing the magnetic field of a permanentmagnet 118. The permanent magnet 118 is made of NbFe35 ceramic materialhowever other materials may be used without departing from the originalscope and spirit of the invention. The coil 119 may then be pulled orpushed away from the permanent magnet 118 depending on the currentpolarity of the coil 119. The coil 119 is coupled to a bobbin 120 and isconstructed from a plurality of small (40AWG) windings. The bobbin 120is composed of several layers of bobbin washers 121. Because bobbin 120is attached to the flexile skin-like material of the inner membrane 107of the pump 100, the coil 119 movement translates into an increase ordecrease of pressure on the medication reservoir 129.

Controlling the amount of electrical current that passes through thecoil 119 produces variable and regulated medication pressure which inturn adjusts the amount of medicating agent passing through a pluralityof injector spines 108 described above. Conversely, the controlledmovement of the coil 119 acts as a pumping function serving to providesuction to the outer membrane 106 of the pump and thus draw insurrounding spinal fluid from the patient.

The apparatus uses a method similar to respiration to not only pumpdrugs into the spinal column containing cancer cells, but also to samplethe immediate area by creating a negative pressure in the samplingcavity 111. As can be seen in FIG. 12, the pump solenoid 104 and pumphead 103 use a magnet 118 and coil 119 as a solenoid to createattraction or repulsion between the pump head 103 and the bobbin 120.This motion is then translated to the pump 100. The outer membrane 106is made of a more ridged durra silicon rubber than the inner membrane107. When the pressure is reversed by the pump solenoid 104, because theinner membrane 107 is softer than the outer membrane 106, the gapbetween the membranes increases and the negative pressure sucks in thespinal fluids through the aspirator micro-pores 112 around the spines108 on the outer membrane 106. Turning back to FIGS. 15 a and 15 b, thissample fluid then gets removed between a sampling washer 115 throughsampling collection ducts 128 in a delivery/sampling head 114 and outthrough a connector plate 113.

The connector plate 113 has both a drug inlet 122 and a sampling tube123 connection. The connector plate 113 also comprises all theelectrical connections for the coil 119, the pressure sensor 131 (shownin FIG. 12) and the temperature sensors 132 (also shown in FIG. 12). Thetop of drug inlet 122 and the sampling tube 123 as well as varioussensor and coil connections can be seen in FIG. 11 b.

FIGS. 16 a and 16 b best show that the electrical connections aretransferred through a series of sensor and coil pins 126 through thedelivery/sampling head 114 to a plurality of sensor and coil connections125 in the inner medication reservoir 129. Connections to the coil 119are made with insulated flexible wire 130 (shown in FIG. 12).

Turning back to FIGS. 16 a and 16 b, the inner and outer membranes 107,106 are attached and compressed by washers 121 to the bobbin 120. Thebobbin 120 freely travels over the permanent NdFeB magnet 118. Themagnet 118 is permanently coupled to the delivery/sampling head 114. Theinner and outer membranes 107, 106 are also coupled directly to thedelivery/sampling head 114. The sampling washer 115 and the bobbin 120also provide the necessary gap of 0.020 inch for the medicationreservoir 129. A compression nut 117 compresses an inner membrane washer116 to clamp the inner membrane 107 against the delivery/sampling head114. As seen in FIG. 15 b, the delivery/sampling head 114 also comprisesa drug dispersion tube 124 which releases the medicating agent ormixture of medicating agents to be administered to the patient into themedication reservoir 129.

Turning back to FIG. 10 a, at the head of the spinal pump 100, the pumphead assembly 103 is coupled to a seal connector 102 via a series offluid lines and electronic connections enclosed in a pump-to-sealinterconnect 101. The seal connector 102 is essentially a valve thatcontrols the amount of fluid that is permitted to enter or leave thepump 100. When more medicating agent is needed, the seal connector 102opens and allows the medicating agent to travel through the pump-to-sealinterconnect 101 and enter the medication reservoir 129 below. When thecorrect amount of medicating agent has been applied, the seal connector102 closes and all incoming fluid flow stops. Additionally, the sealconnector 102 houses a suction nozzle (not shown) that applies suctionto the sampling cavity 111 and draws up recently acquired spinal fluidup and out of the pump 100 and through the seal connector 102.

FIGS. 10 b and 10 c further depict the pump mode 145 and supply mode 144as it is employed by the spinal pump 100. FIGS. 10 b and 10 c depict theelectrostatic muscle 64 in its closed state 134 which is also the supplymode 144, where the medicating agent or BRM are pumped out andtransported from the spinal pump 100 to the desired tumor site orbiological tissue of interest.

In FIG. 10 b, the inlet nozzle is shown as 136, while an increasingchamber volume 141 is taking place. The increase in chamber volumecauses flow 138 from the inlet 136 to enter the chamber 142 and at thesame time, there is a small amount of fluid which flows from the outlet137 into the chamber 142 as well. However, because of the venturi actionof the inlet 136 and the outlet 137, the total net flow is from thespinal pump 100 into the chamber 142. In this case, the inlet 136exhibits a diffuser action 143 and the outlet 137 exhibits a nozzleaction 140.

FIG. 10 c exhibits the electrostatic muscle 64 in its open state 135,which is also the pump mode 145. In this case there is a decrease inchamber volume 151, which causes a net flow to take place from thechamber 150 to the tumor site 41 through the outlet 148. Although thereis a small amount of flow 147, from the chamber 150 to the inlet, thenet flow is substantial and is from the chamber 150 to the tumor site41. In this mode, the inlet 147 exhibits a nozzle action, 152 and theoutlet exhibits a diffuser action 149.

Turning to FIG. 1 a, a delivery hose 200 is coupled to the sealconnector 102 and a chemotherapy pump device (CPD) 1 portion of theapparatus. The delivery hose 200 thus serves as a conduit between thepumping and analyzing portions of the current invention and houses arefill line, a return sample fluid line, and several electronicsconnections for various sensors and the coil 119.

The seal connector 102 is coupled to pump 100 and is firmly embeddedwithin the patient with the top portion of the shunt protruding from thepatient. The delivery hose 200 is coupled to the seal connector 102 andleads away from the pump 100 and up the back of the neck of the patientunderneath the skin. The purpose for maintaining the catheter 200beneath the skin is to give the patient a sense of normalcy andconfidence while they are undergoing treatment.

FIG. 1 b shows an external analyzer unit 300 which communicates with theCPD 1. The CPD 1 communicates with the external analyzer 300 by the useof RF transmitter 304 and its associated antenna 302 and RF receiver 303with its associated antenna 301. After implantation of the CPD 1subcutaneously inside the patient 39, the system allows forprogrammability of the device in order to dispense the medicating agentin proper intervals over time and in the prescribed doses. Once the CPD1 and spinal pump 100 is implanted and is in operation, the clinicianmay decide to change the parameters of the operation such as the amountof medication dispensed onto the tumor site or the time intervalsassociated with the dispense process. The clinician communicates withthe internal electronics of CPD 1 using an external analyzer unit 300shown in FIG. 1 b, which may be in the form of a desktop computer or anyother similar appropriate device. The external analyzer unit 300 is ableto communicate with the microcontroller in CPD 1 through its ownmicrocontroller 305 via RF transmitter 304, its antenna 302, and the RFreceiver 303 and its antenna 301, or via the serial communication port307, located in the external analyzer unit 300. The new sets of commandsare then transferred to the spinal pump 100. These new command data arethen stored in the memory of the microcontroller of CPD 1, which is nowprogrammed anew to perform the procedure as coded in the new instructionset.

In one embodiment, the external analyzer unit 300 is used to implementcomputer software that provides preoperative simulation of the infusionof medicating agents to maximize infusion efficiency and minimize localtoxicity by means of a diffusion model. The drug diffusion model (DDM)takes into account the brain geometry, the way CSF is produced in thechoroid plexus from the blood and also from the brain tissue from whichit is believed to seep through the porous extracellular space towardsthe ventricles, as well as the CSF flow through the ventricles and SAS.This model does not consider other intracranial dynamics conditions suchas the pulsating CSF motion due to expansion of the parenchyma andchoroid plexus in the systole during a cardiac cycle.

In the first step, the patient-specific MRI is used to extract theanatomically accurate geometry of CSF spaces inside the brain, as wellas the CSF flow velocities in select regions of the brain. In the secondstep, the brain region is partitioned into small discrete volume grids.In the third step, a set of equations and boundary conditions describeflow physics and mass transfer between the finite volumes in the brainregion. In the final step, the equations are solved numerically over thefinite volume and the boundaries between the adjacent volumes.

The patient specific brain imaging data not only permits reconstructionof physiologically accurate substructures and boundaries between regionsin the brain, but also enables measuring CSF flow fields and velocitiesin vivo. Brain properties such as porosity, diffusivity, andpermeability, as well as CSF parameters such as viscosity and densitycan be estimated from the brain location and reference literature. Theseparameters combined with basic fluid physics enable quantification ofthe multidirectional CSF flow fields that are consistent with theclinical observation in major CSF pathway sections of the brain.

The brain including SAS is partitioned into small triangular andquadrilateral elements by applying Delaunay triangulation. The braintissue is assumed to be a homogeneous isotropic porous medium forsimplicity. Each small finite volume is linked to its neighbors so as toform a logically connected computational mesh, which can be generated bycommercial grid generator tools such as Gambit. The grid sizes need tobe large enough to minimize the number of volume elements forcalculations yet small enough to be able to spatially resolve theanatomical properties of the tumor area. A typical simulation consistsof approximately 100,000 volume elements distributed throughout thebrain. The flow and mass transfer equations are enforced over thecomputational domain consisting of these meshes.

The drug delivery to the ventricles is simply modeled as insertingaqueous solution consisting of drug solutes via an infusion catheterinto a large pool of CSF, which naturally flows and interacts withsurrounding porous brain tissues. Both CSF and drug solution are assumedto be incompressible Newtonian fluids whose motion inside the brain canbe described by the mass and momentum conservation equation.Additionally, the drug diffusion is described by the species transportand chemical kinetics equations. The drug diffusion model consists offour parts: the flow inside the catheter, the flow in the ventricularand subarachnoid systems, the flow in porous brain tissues, and theboundary conditions for intracranial dynamics between the CSF andvarious brain tissues.

For the flow inside the catheter, the model divides the space inside thelumen of the catheter into small finite elements. The fluid flow betweenthe finite elements is modeled with the continuity and Navier-Stokesequations as shown in Equations 1 and 2, respectively. The continuityequation (Eq 1) describes that the drug fluid is incompressible.{right arrow over (∇)}·(ρ_(f){right arrow over (ν)}_(f))=0  (1)

The Navier-Stokes equation (Eq 2) describes that the momentum of thefluid flow is conserved. It states that any change in fluid velocity inthe catheter (the left-hand side of the equation) is due to the pressuregradient (caused by the pumps) and resistance of the flow due to fluidviscosity.

$\begin{matrix}{{\rho_{f}\left( {\frac{\partial{\overset{->}{v}}_{f}}{\partial t} + {{\overset{->}{v}}_{f} \cdot {\overset{->}{\nabla}{\overset{->}{v}}_{f}}}} \right)} = {{- {\overset{->}{\nabla}p}} + {\mu_{f}{{\overset{->}{\nabla}}^{2}{\overset{->}{v}}_{f}}}}} & (2)\end{matrix}$

The movement of the drug molecules inside the catheter due to the flowcan be modeled with the species transport equation as shown in Equation3. It states that the change in concentration of the molecules due todiffusion and convection (the left-hand side of the equation) depends onthe divergent of the product of the diffusivity and concentrationgradient of the molecules in the fluid.

$\begin{matrix}{{\frac{\partial C_{f}}{\partial t} + {{\overset{->}{v}}_{f} \cdot {\overset{->}{\nabla}C_{f}}}} = {\overset{->}{\nabla}{\cdot \left( {D_{b}{\overset{->}{\nabla}C_{f}}} \right)}}} & (3)\end{matrix}$

The fluid flow inside the ventricles is dictated by the natural CSF flowin the ventricular and subarachnoid systems. At the tip of the catheter,the CSF velocity is the same as the fluid velocity coming out of thecatheter: {right arrow over (ν)}_(c)={right arrow over (ν)}_(f). Becausethe CSF is also assumed to be an incompressible Newtonian fluid, the CSFmotion can be described by the continuity and the Navier-Stokesequations as shown in Equations 4 and 5, respectively. The continuityequation (Eq 1) describes the conservation of mass of CSF.{right arrow over (∇)}·(ρ_(c){right arrow over (ν)}_(c))=0  (4)

The conservation momentum of the fluid flow is described byNavier-Stokes equation (Eq 5). It states that any change in fluidvelocity in the ventricular and subarachnoid systems (the left-hand sideof the equation) is due to the pressure gradient (between ventricles andSASs) and resistance of the flow due to CSF viscosity.

$\begin{matrix}{{\rho_{c}\left( {\frac{\partial{\overset{->}{v}}_{c}}{\partial t} + {{\overset{->}{v}}_{c} \cdot {\overset{->}{\nabla}{\overset{->}{v}}_{c}}}} \right)} = {{- {\overset{->}{\nabla}p}} + {\mu_{c}{{\overset{->}{\nabla}}^{2}{\overset{->}{v}}_{c}}}}} & (5)\end{matrix}$

Like in Equation 3, the movement of the drug molecules inside theventricles and SASs due to the flow can be modeled with the speciestransport equation as shown in Equation 6. It states that the change inconcentration of the molecules due to diffusion and convection (theleft-hand side of the equation) depends on the divergent of the productof the diffusivity and concentration gradient of the molecules in theCSF.

$\begin{matrix}{{\frac{\partial C_{f}}{\partial t} + {{\overset{->}{v}}_{c} \cdot {\overset{->}{\nabla}C_{f}}}} = {\overset{->}{\nabla}{\cdot \left( {D_{c}{\overset{->}{\nabla}C_{f}}} \right)}}} & (6)\end{matrix}$

The fluid flow inside the brain tissues is modeled as the fluid flow ina porous medium. The brain is partitioned into small finite elements andthe flow between these elements is modeled with the continuity equationand Darcy's Law as shown in Equations 7 and 8, respectively. Thecontinuity equation (Eq 8) describes that the loss of fluid in the flowis due to the absorption into the porous medium. The fluid velocity intissue is related to average CSF velocity, {right arrow over(ν)}_(t)=ε{right arrow over (ν)}_(c) through the porosity of braintissue. The amount of fluid loss captured in the sink term is a functionof the difference between the interstitial fluid pressure and the venouspressure: S_(B)=f(p−p_(v)).{right arrow over (∇)}·(ρ_(c){right arrow over (ν)}_(t))=S _(B)  (7)

The fluid dynamics in the porous brain tissue is embodied in the Darcy'sLaw (Eq 8), which states that the momentum of the fluid flow isconserved. It states that any change in fluid velocity in the brain (theleft-hand side of the equation) is due to the pressure gradient (causedby the pressure drop in the porous medium) and resistance of the mediumto the flow.

$\begin{matrix}{{\frac{\rho_{c}}{ɛ}\left( {\frac{\partial{\overset{->}{v}}_{i}}{\partial t} + {{ɛ^{- 1}\left( {{\overset{->}{v}}_{t} \cdot \overset{->}{\nabla}} \right)}{{\overset{->}{v}}_{t} \cdot}}} \right)} = {{- {\overset{->}{\nabla}p}} - {\Re^{- 1}{\overset{->}{v}}_{t}}}} & (8)\end{matrix}$

where the resistance of the porous brain tissue can be defined as

${\Re^{- 1}{\overset{->}{v}}_{t}} = {{\frac{\mu_{c}}{k}{\overset{->}{v}}_{t}} + {\frac{\beta\rho}{2}{\overset{->}{v}}_{t}^{2}} - {\mu_{c}{{\overset{->}{\nabla}}^{2}{\overset{->}{v}}_{t}}}}$

The movement of the drug molecules inside the brain tissue due to theflow described in Eq 8 can be modeled with the species transportequation as shown in Equation 9. It states that the change inconcentration of the molecules due to diffusion and convection (theleft-hand side of the equation) depends on the divergent of the productof the diffusivity tensor of the brain medium and concentration gradientof the molecules in the fluid. The accuracy of the model can be improvedby incorporating the loss of drug molecules due to decomposition andbio-elimination.

$\begin{matrix}{{{ɛ\frac{\partial C_{t}}{\partial t}} + {{\overset{->}{v}}_{t} \cdot {\overset{->}{\nabla}C_{t}}}} = {{\overset{->}{\nabla}{\cdot \left( {D_{o}{\overset{->}{\nabla}C_{t}}} \right)}} + {R\left( {C_{t},\overset{->}{x}} \right)} + {S\left( {C_{t},\overset{->}{x}} \right)}}} & (9)\end{matrix}$

The completeness of the diffusion model is captured in the boundarycondition assumptions listed below. At the catheter inlet, the infusionflow rate or pressure and concentration of drug are assumed to beconstant. At the interior wall inside the lumen of the catheter, theflow is assumed no slip,

${\frac{\partial p}{\partial n} = 0},$and the drug doesn't penetrate (zero flux) into the catheter wall,{right arrow over (n)}·{right arrow over (∇)}C_(f)=0 and {right arrowover (ν)}_(f)=0. At the outer surface of the catheter, the same boundaryconditions are assumed as in the inside. At the catheter tip, thecontinuity of flow is assumed: {right arrow over(ν)}_(f)|_(lumen)={right arrow over (ν)}_(Cout)={right arrow over(ν)}_(t), and, p_(lumen)=p_(Cout), and C_(f)|_(lumen)=C_(t). At theventricles or SASs, the fluid pressure is the same as the pressure ofthe Cerebrospinal fluid (CSF). Bio-elimination “sink term” is assumed asa function of the difference between interstitial pressure and venouspressure: S_(B)=f(p−p_(v)).

The nine partial differential equations (Eq 1-9) are applied to thediscrete volumes in the model to produce a set of non-linear algebraicequations for the entire brain model. These equations are solved withproper boundary condition using the iterative Newton-Krylov method andsimulated using commercial fluid dynamics software such as Fluent.

The microcontroller located in CPD 1 and implanted inside the patient'sbody 39 communicates with the external analyzer unit 300 via RFtransmitter 304 and RF receiver 303 thereby sending its collected datato the external analyzer unit 300. This feature enables the clinician tocollect data and to determine the state of the patient throughout theperiod of treatment. These data are stored inside the external analyzerunit 300 providing chart history of the treatment status of theparameters associated with the tumor site. The CPD 1 transmits data forcollection and storage. The external analyzer unit 300 is controlled bythe user via the settings in control 308 and it also displays the amountof medicating agent dispensed over time by the spinal pump 100 on itsdisplay 309. Data collected in this manner can be used to correlatebehavior pattern of a particular patient and his or her chart history.One can write a data collection and analysis program which can bedisplayed by the external analyzer unit 300. Once the data are collectedfrom the CPD 1, the external analyzer unit 300 or the host PC can thenplot the data on a time scale and analyze the data further. It issignificantly better to correlate between the input and the output orbetween cause and effect to mirror the action of the pump 100 and itshost tumor site. Such data in the form of historical plot of cause andeffect benefit the patient 39 and aide in future research. The entireunit as shown in FIG. 1 b is run by power obtained from its power source306.

FIG. 1 c is an illustration of a patient 39 with tumor caused byleptomeningeal carcinomatosis with the implanted pump 100. The externalanalyzer unit 300 with its associated serial port 307 and receiver andtransmitter antennae 301 and 302 respectively is shown in itsbidirectional communication model with the implanted CPD 1 via the RFpath 310.

Turning to FIG. 4 a, the CPD 1 comprises a delivery connector 7 wherethe delivery hose 200 couples with the CPD 1. The delivery connector 7contains a drug outlet 4, a sample return 5, and a plurality of sensorconnections 6 for controlling the pump unit 100 and for analyzing thesample fluid that is obtained from the spine of the patient. The drugoutlet 4 is the aperture in which a medicating agent or mixtures ofmedicating agents are sent from the CPD 1 through the delivery hose 200.Similarly, the sample return 5 is the aperture where spinal fluid thathas been collected by pump 100 is returned by the delivery hose 200 andenters the CPD 1 for analysis. The process by which the external CPD 1sends a medicating agent or mix of medicating agents and receives samplefluid obtained from the patient through the delivery hose 200 isexplained in further detail below.

Up to four drug ampoules 2 (FIG. 2) can be deposed on the bottom portion10 of the external CPD 1 in four separate ampoule bays 8 as depicted inFIG. 3 d. It is to be expressly understood that fewer or additionalampoule bays may be present without departing from the original spiritand scope of the invention. To introduce medicating agent into the CPD1, a drug ampoule 2 is inserted into the ampoule bay 8. Drug needles 18extending from the interior of the CPD 1 shown in FIG. 7 a penetrate theampoules 2 and carry the medicating agent. The CPD 1 then draws in themedicating agent in a series of steps that are described below.

Turning to FIG. 6, the interior of the CPD 1 is comprised of twoassemblies; a pump electronics assembly 12 and an induction chargerassembly 11. The pump electronics assembly 12 and the induction chargerassembly 11 are both housed within the external CPD 1 and are joined byan electronics interconnect cable 13 as best seen in FIGS. 7 a and 7 b.

The pump electronics assembly 12 is shown in greater detail in FIGS. 8 aand 8 b. As seen in FIG. 8 b, the pump electronics assembly 12 containsa drug delivery CPU 27 that stores its program and data into two FLASHmemories 28. Pre-stored information such as look-up tables and the likeare stored on the FLASH memories 28. The drug delivery CPU 27 runs apre-installed intelligent chemo delivery software program and controlsan ampoule pump integrated circuit 20, a return pump integrated circuit19, and a delivery valve drift integrated circuit 22 as seen in FIG. 8a. The drug delivery CPU 27 also communicates with a lab-on-a-chip 21and receives important treatment data such as sample temperature datathrough the sensor inputs 6 in the delivery connector 7 seen best inFIG. 6.

The drug delivery CPU 27 is pre-programmed and is capable oftransmitting data through a Bluetooth® transceiver 29. The Bluetoothtransceiver 29 is connected to a Bluetooth® antenna 30: A user orqualified physician who wishes to change the patient's drug regimen froma remote location first sends the data to the patient. The sentinformation is then picked up by the Bluetooth® transceiver 29 andantenna 30 and is then stored on the FLASH memory chips 28. When thedrug delivery CPU 27 retrieves information from the FLASH memory chips28 it adjusts the drug regimen (dose, scheduling, etc.) according to theuser's data instructions.

The external CPD 1 is capable of delivering up to four different drugssimultaneously with high accuracy in the following manner: The pumpelectronics assembly 12 of FIG. 8 a comprises up to four piezoelectricpumps 17 driven by a corresponding ampoule pump integrated circuit 20that together pump the medicating agent out of the ampoule 2. The useand manufacture of piezo pumps are well known to those in the art. Feweror additional piezo pumps 17 than what is depicted in FIG. 8 a may beused without departing from the original spirit and scope of theinvention. The pump needles 18 are sufficiently long enough so that whena drug ampoule 2 is attached to the piezo pump 17 as depicted in FIG. 2,the medicating agent at the bottom of the ampoule may be accessed. Pumpneedles 18 coupled to the piezoelectric pumps 17 penetrate the ampoules2 and the piezoelectric pump 17 pumps the medicating agent through adrug manifold tube 24 and into a delivery valve 15 and out through thedrug delivery connector 7. The delivery valve 15 is regulated by adelivery valve driver integrated circuit 22 which is controlled by thedrug delivery CPU 27. The medicating agent, after being pumped throughthe delivery connector 7, then enters into the delivery hose connector37 (FIG. 5) via the drug output 4 on the delivery connector 7 depictedin FIG. 4 b. The medicating agent is then pumped through the deliveryhose 200 and into the spinal pump unit 100 via the seal connector 102.In FIG. 5, the delivery hose 200 couples to the CPD 1 via a deliveryhose connector 37.

The external CPD 1 is fully programmable and runs intelligent softwareto determine what and how much drug is required. The regulation loop ofthe intelligent drug delivery system uses a return sample of fluids fromthe “delivery area” to determine the necessary response. In FIG. 5, thereturn sample fluid obtained from the patient travels through thedelivery hose 200, through the delivery hose connector 37, and thenenters delivery connector 7 through the sample return 5 as shown in FIG.4 b. Turning to FIG. 8 a, after the sample fluid passes from thedelivery connector 7, the sample fluid enters the delivery valve 15. Thenegative pressure necessary to pump the sample is created by the returnpiezoelectric pump 16 that is powered by a return pump driver integratedcircuit 19. The fluid sample then travels from the delivery valve 15into a return pump input tube 25 and into a lab-on-a-chip 21 that sensesthe chemical composition of the sample. The return piezoelectric pump 16continues pumping the sample fluid through itself and back out into areturn output pump tube 23. The sample fluid is then mixed together withthe delivery drug in the delivery valve 15, to continue a closed loopcycle to be returned to the collection site.

The second main assembly, the induction charger assembly 11, is depictedin greater detail in FIGS. 9 a and 9 b. The induction charger assembly11 provides with a means for charging a lithium ion battery 14 (shown inFIG. 5). An induction coil 38 coupled to the induction chargerelectronics assembly 11 receives a high frequency (50 Khz) inducedmagnetic field from a similar charging coil from an external batterycharger device (not shown). The induction coil 38 is coupled to arectifier 35 shown in FIG. 9 b. The rectifier 35 converts the highfrequency voltage to a DC voltage that is filtered by an inductor 34 andcapacitors 33. A battery charger controller 32 regulates the charging ofthe battery 14. The charger connector 36 is both for powering theelectronics as well as charging the lithium ion battery 14. The battery14 is appropriately sized to provide sufficient power for days ofservice without the need of charging.

The lithium ion battery 14 preferably has an “L” shape as shown in FIG.6 so as to leave sufficient space available for the pump needles 18 anddrug ampoules 2 within the housing of the CPD 1 and is sized to providesufficient power for days of service without the need of re-charging.However it is to be expressly understood that other varieties ofbatteries with various life spans and shapes may also be used withoutdeparting from the original scope and spirit of the invention. Thelithium ion battery 14 is coupled directly to the housing of the CPD 1and is removable so that when the stored energy has been depleted fromthe battery 14, it may be easily replaced.

Filling the ampoules 2 with medicating agent and having the medicatingagent then delivered intratumor by the pump 100 and its injector spines108, eliminates the blood barrier as a potential obstacle. As discussedabove, most medicating agents would normally have a difficult timegetting to the cancer cells directly without the pump 100 penetratingthe blood barrier. Delivering the medicating agent directly into thetumor also allows for more concentrated doses which eliminates the sideeffects associated with the systemic intravenous delivery of medicatingagents listed above, including hydrocephalus which can be catastrophicto the patient. Finally, the pump 100 eliminates the need for repeatpuncture of the Ommaya reservoir or repeat lumbar punctures, thusimproving patient safety from risk of infection or discomfort fromrepeat lumbar punctures.

In patients in whom a resection cannot be performed, an alternativeembodiment of the current invention involving a multidelivery catheter200 is employed. A method for delivering a medicating agent into thecerebrospinal fluid (CSF) in a patient comprises surgically implanting amultidelivery catheter 200 beneath the skin of the patient into atreatment site. The multidelivery catheter 200 is then coupled to anexternal analyzer unit 300. The external analyzer unit 300 is the sameexternal analyzer unit 300 described above with regard to the previousembodiment. The multidelivery catheter 200 is then operated within theCSF of the patient in order to infuse the medicating agent to thetreatment site. The multidelivery catheter 200 is then used to suctionin a sample of the CSF from the treatment site and transfer it to theexternal analyzer unit 300. In the same manner as described above withregard to the previous embodiment, the external analyzer unit 300 isthen used to track and monitor the progress of the patient's treatmentvia the external analyzer unit 300. Additionally in the same manner asdescribed above with the previous embodiment, the external analyzer unit300 comprises the means for altering and changing the patient'streatment. Finally, a reservoir of medicating agent located within theexternal analyzer unit 300 may be refilled and replenished as needed.

Also as similarly described above, the external analyzer unit 300comprises means for displaying the amount of medicating agent dispensedover time by the multidelivery catheter 200 within the treatment site.

In one particular embodiment, the suctioning in of the sample CSF fromthe treatment site comprises suctioning in the sample CSF in at leasttwo proximal ports (not shown) defined in the proximal end of themultidelivery catheter 200. The means for tracking and monitoring theprogress of the patient's treatment by the external analyzer unit 300further comprises passing the sample CSF through a means for spinalfluid analysis in the external analyzer unit 300. The sample of CSFpasses through a means of analysis on the external analyzer unit 300that comprises means for measuring the effectiveness of theadministration of the medicating agent.

In another embodiment, the method step of measuring the effectiveness ofthe medicating agent administration further comprises displaying theresults obtained from the means of the analyzer unit on a display.

In an alternative embodiment, the external analyzer unit 300 furthercomprises means for providing a preoperative simulation of the infusionof the medicating agent to maximize efficiency and minimize toxicity bymeans of a diffusion model.

The external analyzer unit 300 further comprises entering commandfunctions and data into the external analyzer unit 300 from a remotekeypad (not shown) and displaying the commands on a display 309. Theentering of command functions may comprise sending command functions anddata to the external analyzer unit 300 by means of a Bluetooth®transceiver and antenna.

The refilling and replacing of the reservoir of medicating agent locatedin the analyzer unit also comprises refilling and replacing at leastfour drug ampoules coupled to the analyzer unit.

FIG. 17 is a functional circuit diagram further illustrating therelationship between the elements of CPD 1 described above.

It is to be expressly understood that the disclosed device may also beused to treat cranial neuropathies associated with leptomeningealcarcinomatosis secondary to cancer seeding on the cranial nerves. Suchneuropathies include but are not limited to facial paralysis, diplopia,and difficulty swallowing. Due to the current device's ability toadminister more than one medicating agent at a time, treatment of thesecranial neuropathies may be carried out separately or concurrently withthe treatment of the cancer cells contained within the spinal fluid of apatient as described above.

Many alterations and modifications may be made by those having ordinaryskill in the art without departing from the spirit and scope of theinvention. Therefore, it must be understood that the illustratedembodiment has been set forth only for the purposes of example and thatit should not be taken as limiting the invention as defined by thefollowing invention and its various embodiments.

For example, one skilled in the art may produce a device with fewer oradditional drug ampoule bays or piezoelectric pumps without departingfrom the original scope and spirit of the invention.

Therefore, it must be understood that the illustrated embodiment hasbeen set forth only for the purposes of example and that it should notbe taken as limiting the invention as defined by the following claims.For example, notwithstanding the fact that the elements of a claim areset forth below in a certain combination, it must be expresslyunderstood that the invention includes other combinations of fewer, moreor different elements, which are disclosed in above even when notinitially claimed in such combinations. A teaching that two elements arecombined in a claimed combination is further to be understood as alsoallowing for a claimed combination in which the two elements are notcombined with each other, but may be used alone or combined in othercombinations. The excision of any disclosed element of the invention isexplicitly contemplated as within the scope of the invention.

The words used in this specification to describe the invention and itsvarious embodiments are to be understood not only in the sense of theircommonly defined meanings, but to include by special definition in thisspecification structure, material or acts beyond the scope of thecommonly defined meanings. Thus if an element can be understood in thecontext of this specification as including more than one meaning, thenits use in a claim must be understood as being generic to all possiblemeanings supported by the specification and by the word itself.

The definitions of the words or elements of the following claims are,therefore, defined in this specification to include not only thecombination of elements which are literally set forth, but allequivalent structure, material or acts for performing substantially thesame function in substantially the same way to obtain substantially thesame result. In this sense it is therefore contemplated that anequivalent substitution of two or more elements may be made for any oneof the elements in the claims below or that a single element may besubstituted for two or more elements in a claim. Although elements maybe described above as acting in certain combinations and even initiallyclaimed as such, it is to be expressly understood that one or moreelements from a claimed combination can in some cases be excised fromthe combination and that the claimed combination may be directed to asubcombination or variation of a subcombination.

Insubstantial changes from the claimed subject matter as viewed by aperson with ordinary skill in the art, now known or later devised, areexpressly contemplated as being equivalently within the scope of theclaims. Therefore, obvious substitutions now or later known to one withordinary skill in the art are defined to be within the scope of thedefined elements.

The claims are thus to be understood to include what is specificallyillustrated and described above, what is conceptionally equivalent, whatcan be obviously substituted and also what essentially incorporates theessential idea of the invention.

1. A method for delivering medicating agent into the cerebrospinal fluid(CSF) in a patient comprising: surgically implanting a catheter into theCSF of the patient at a defined treatment site; coupling the distal endof the catheter to a magnetically operated spinal pump disposed at thetreatment site; coupling the proximal end of the catheter to an analyzerunit disposed outside of the treatment site; operating the pump withinthe CSF of the patient in order to infuse medicating agent to thetreatment site under control of the analyzer unit; suctioning in asample of the CSF from the treatment site and transferring the CSFsample to the analyzer unit; tracking and monitoring the progress of thepatient's treatment via the analyzer unit; altering and changing thepatient's treatment proactively by controlling the analyzer unit via anexternal controller communicated to the analyzer unit by an RF link, theexternal controller comprising means for allowing proactive alterationof the delivery schedule of medicating agents to the treatment site ofthe patient by the spinal pump based on measurements of a plurality ofparameters obtained from the spinal pump and quantified by the analyzerunit; displaying the parameter measurements on a display coupled to theexternal controller; and refilling and replacing a reservoir ofmedicating agent located in the analyzer unit, wherein suctioning in thesample of the CSF further comprises suctioning the sample of the CSF ata variable rate into an intra-membrane reservoir defined between anouter and inner membrane in the spinal pump by the oscillation of amagnetic solenoid and a plurality of pores defined within the surface ofthe outer membrane and around each distal tip of a plurality of hollowneedles coupled to inner membrane.
 2. The method of claim 1 whereoperating the magnetically operated spinal pump comprises: contractingand expanding a plurality of hollow needles fluidly coupled to an innermembrane reservoir in the spinal pump by oscillation of a magneticsolenoid; extending the plurality of hollow needles through an outermembrane and an intra-membrane reservoir defined between the outermembrane and inner membrane reservoir when the inner membrane is beingexpanded; retracting the plurality of hollow needles through the outermembrane and the intra-membrane reservoir defined between the outermembrane and the inner membrane reservoir when the inner membranereservoir is being contracted such that the distal ends of the pluralityof hollow needles do not retract past the outer membrane; and preventingany fluid communication between the inner membrane reservoir and theintra-membrane reservoir.
 3. The method of claim 1 where tracking andmonitoring the progress of the patient's treatment further comprisespassing the sample of the CSF through a lab-on-a-chip in the analyzerunit.
 4. The method of claim 3 where passing the sample of the CSFthrough a lab-on-a-chip further comprises measuring the effectiveness ofintratumoral medicating agent administration by the lab-on-a-chip. 5.The method of claim 4 where measuring the effectiveness of intratumoralmedicating agent administration further comprises displaying the resultsobtained from the lab-on-a-chip on a display.
 6. The method of claim 1further comprising providing a preoperative simulation of the infusionof the medicating agent to maximize efficiency and minimize toxicity bymeans of a diffusion model.
 7. The method of claim 1 where altering andchanging the patient's treatment by controlling the analyzer unitfurther comprises entering command functions and data into the analyzerunit from a remote keypad and displaying the commands on a display. 8.The method of claim 7 where altering and changing the patient'streatment by controlling the analyzer unit further comprises sendingcommand functions and data to the analyzer unit by means of a wirelesstransceiver and antenna.
 9. The method of claim 1 where refilling andreplacing the reservoir of medicating agent located in the analyzer unitfurther comprises refilling and replacing at least four drug ampoulescoupled to the analyzer unit.
 10. A method for delivering a medicatingagent into the cerebrospinal fluid (CSF) in a patient comprising:surgically implanting a multidelivery catheter beneath the skin of thepatient into a treatment site; coupling the multidelivery catheter to ananalyzer unit disposed outside of the treatment site; operating themultidelivery catheter within the CSF of the patient in order to infusethe medicating agent to the treatment site under control of the analyzerunit; suctioning in a sample of the CSF from the treatment site andtransferring it to the analyzer unit; tracking and monitoring theprogress of the patient's treatment via the analyzer unit; altering andchanging the patient's treatment by controlling the analyzer unit via anexternal controller communicated to the analyzer unit by an RF link, theexternal controller allowing proactive alteration of a delivery scheduleof medicating agents to the treatment site of the patient by themultidelivery catheter based on measurements of a plurality ofbiological parameters obtained from the multidelivery catheter andquantified by the analyzer unit; displaying the biological parametersmeasurements on a display coupled to the external controller; andrefilling and replacing a reservoir of medicating agent located in theanalyzer unit, where suctioning in the sample of the CSF from thetreatment site comprises suctioning in the sample of the CSF at avariable rate in at least two proximal ports defined in the proximal endof the multidelivery catheter.
 11. The method of claim 10 where trackingand monitoring the progress of the patient's treatment via the analyzerunit further comprises displaying the amount of medicating agentdispensed over time by the multidelivery catheter within the treatmentsite.
 12. The method of claim 10 where tracking and monitoring theprogress of the patient's treatment further comprises passing the sampleof the CSF through a lab-on-a-chip in the analyzer unit.
 13. The methodof claim 12 where passing the sample of the CSF through a lab-on-a-chipfurther comprises measuring the effectiveness of the medicating agentadministration with the lab-on-a-chip.
 14. The method of claim 13 wheremeasuring the effectiveness of the medicating agent administrationfurther comprises displaying the results obtained from the lab-on-a-chipon a display.
 15. The method of claim 10 further comprising providing apreoperative simulation of the infusion of the medicating agent tomaximize efficiency and minimize toxicity by means of a diffusion model.16. The method of claim 10 where altering and changing the patient'streatment by controlling the analyzer unit further comprises enteringcommand functions and data into the analyzer unit from a remote keypadand displaying the commands on a display.
 17. The method of claim 16where altering and changing the patient's treatment by controlling theanalyzer unit further comprises sending command functions and data tothe analyzer unit by means of a wireless transceiver and antenna. 18.The method of claim 10 where refilling and replacing the reservoir ofmedicating agent located in the analyzer unit further comprisesrefilling and replacing at least four drug ampoules coupled to theanalyzer unit.